The present invention relates to 7-alkyl- and cycloalkyl-substituted imidazotriazinones, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The published specification DE-28 11 780 describes imidazotriazines as bronchodilators having spasmolytic activity and inhibitory activity against phosphodiesterases which metabolize cyclic adenosine monophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-III and PDE-IV). An inhibitory action against phosphodiesterases which metabolize cyclic guanosine monophosphate (cGMP-PDEs, nomenclature according to Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) PDE-I, PDE-II and PDE-V) has not been described. Compounds having a sulphonamide group in the aryl radical in the 2 position are not claimed. Furthermore, FR 22 13 058, CH-59 46 71, DE-22 55 172, DE-23 64 076 and EP-000 9384 describe imidazotriazinones which do not have a substituted aryl radical in the 2 position and are likewise said to be bronchodilators having cAMP-PDE-inhibitory action.
The compounds according to the invention are potent inhibitors either of one or of more of the phosphodiesterases which metabolize cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP-PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) these are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
An increase in the cGMP concentration can lead to beneficial antiaggregatory, antithrombotic, antiprolific, antivasospastic, vasodilative, natriuretic and diuretic effects. It can influence the short- or long-term modulation of muscular and cardiac inotropy, of the pulse and of cardiac conduction (J. C. Stoclet, T. Keravis, N. Komas and C. Lugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).
The present invention, accordingly, provides 7-alkyl- and cycloalkyl-substituted imidazotriazinones of the general formula (I) 
in which
R1 represents straight-chain or branched alkyl having up to 4 carbon atoms,
R2 represents straight-chain alkyl having at least 5 carbon atoms or branched alkyl having at least 3 carbon atoms, or represents cycloalkyl having 3 to 10 carbon atoms,
R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 8 carbon atoms, or represent a straight-chain or branched alkyl chain having up to 10 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 6 carbon atoms and/or by radicals of the formulae xe2x80x94SO3H, xe2x80x94(A)axe2x80x94NR7R8, xe2x80x94Oxe2x80x94COxe2x80x94NR7xe2x80x2R8xe2x80x2, xe2x80x94S(O) bxe2x80x94R9, HNxe2x95x90SOxe2x80x94R9xe2x80x2, xe2x80x94P(O)(OR10)(OR11), 
xe2x80x83in which
a and b are identical or different and represent a number 0 or 1,
A represents a radical CO or SO2,
R7, R7xe2x80x2, R8 and R8xe2x80x2 are identical or different and represent hydrogen, or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula xe2x80x94(SO2)cxe2x80x94NR12R13,
in which
c represents a number 0 or 1,
R12 and R13 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms,
or
R7, R7xe2x80x2, R8 and R8xe2x80x2 represent straight-chain or branched alkoxy having up to 6 carbon atoms, or represent straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, aryl having from 6 to 10 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula xe2x80x94(CO)dxe2x80x94NR14R15,
in which
R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms. and
d represents a number 0 or 1, or
R7 and R8 and/or R7xe2x80x2 and R8xe2x80x2 together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula xe2x80x94NR16,
xe2x80x83in which
R16 represents hydrogen, aryl having 6 to 10 carbon atoms, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl,
R9 and R9xe2x80x2 are identical or different and represent aryl having 6 to 10 carbon atoms or benzyl, or represent straight-chain or branched alkyl having up to 4 carbon atoms,
R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and/or the alkyl chain listed above under R3/R4 is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 ring heteroatoms from the group consisting of S, N, O or a radical of the formula xe2x80x94NR17, where the alkyl chain may optionally also be attached via a ring nitrogen atom,
xe2x80x83in which
R17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms,
and where aryl and the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of nitro, halogen, xe2x80x94SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula xe2x80x94(SO2)exe2x80x94R18R19,
in which
e represents a number 0 or 1,
R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 6 carbon atoms,
and/or
R3 or R4 represent radicals of the formulae xe2x80x94NR20R21 or xe2x80x94(O)xe2x80x94Exe2x80x94NR22R23,
in which
R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a 5- or 6-membered saturated heterocycle having a further ring heterocycle from the group consisting of S and O or a radical xe2x80x94NR24,
in which
R24 has the meaning of R16 given above and is identical to or different from this meaning,
E is a straight-chain alkylene group having up to 5 carbon atoms,
R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning,
and/or
R3 or R4 represent radicals of the formulae 
xe2x80x83or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered partially unsaturated, saturated and unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N, O or a radical of the formula xe2x80x94NR25 which may optionally also be attached via a ring nitrogen atom,
in which
R25 has the meaning of R16 given above and is identical to or different from this meaning, or represents carboxyl, formyl or straight-chain or branched acyl having up to 5 carbon atoms,
and where cycloalkyl, aryl and/or the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and/or by groups of the formulae xe2x80x94SO3H, xe2x80x94OR26, (SO2)fNR27R28, xe2x80x94P(O)(OR29)(OR30),
in which
R26 represents a radical of the formula 
xe2x80x83represents cycloalkyl having 3 to 7 carbon atoms, or hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen,
f is a number 0 or 1,
R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula xe2x80x94COxe2x80x94NH2,
R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
and/or cycloalkyl, aryl and/or the heterocycle are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, carboxyl, by a 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O or by groups of the formulae xe2x80x94SO2xe2x80x94R31, P(O)(OR32)(OR33) or xe2x80x94NR34R35,
in which
R31 is hydrogen or has the meaning of R9 given above and is identical to or different from this meaning,
R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or
R34 and R35 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from the group consisting of S and O or a radical of the formula xe2x80x94NR36,
in which
R36 has the meaning of R16 given above and is identical to or different from this meaning,
or
R3 and R4 together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N, O or a radical of the formula xe2x80x94NR37,
in which
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms,
or
R37 represents a radical of the formula xe2x80x94(CO)gxe2x80x94G,
in which
g represents a number 0 or 1,
G represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 6 carbon atoms, hydroxyl and trifluoromethyl,
and the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 6 carbon atoms and groups of the formulae xe2x80x94P(O)(OR38)(OR39) and xe2x80x94(CO)g)xe2x80x94NR40R41,
in which
R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
g represents a number 0 or 1,
and
R40 and R41 are identical or different and have the meaning of R18 and R19 given above,
and/or the heterocycle mentioned under R3 and R4, formed via the nitrogen, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a radical of the formula xe2x80x94SO3H, xe2x80x94NR42R43 or P(O)OR44OR45,
in which
R42 and R43 are identical or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
R44 and R45 are identical or different and have the meaning of R10 and R11 given above,
and/or the alkyl is optionally substituted by benzyloxy or aryl having 6 to 10 carbon atoms, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy or alkylthio having in each case up to 6 carbon atoms, or by a group of the formula xe2x80x94NR42xe2x80x2R43xe2x80x2,
in which
R42xe2x80x2 and R43xe2x80x2 have the meaning of R42 and R43 given above and are identical to or different from this meaning,
and/or the heterocycle mentioned under R3 and R4, formed via a nitrogen atom, is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 ring heteroatoms from the group consisting of S, N and/or O, optionally also attached via an N function, where the ring systems for their part may be substituted by halogen, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms,
or
R3 and R4 together with the nitrogen atom form radicals of the formulae 
xe2x80x83in which
R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 6 carbon atoms,
R45 and R45xe2x80x2 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R46 represents hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms,
R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxy or represents straight-chain or branched alkoxy having up to 6 carbon atoms,
and their salts and isomeric forms.
The compounds according to the invention may exist in stereoisomeric forms which are either like image and mirror image (enantiomers), or which are not like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms can, just like the diastereomers, be separated in a known manner into the stereoisomerically uniform constituents.
The substances according to the invention may also be present as salts. In the context of the invention, preference is given to physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
In the context of the invention and depending on the various substituents, optionally benzo-fused heterocycle generally represents an aromatic, saturated, partially unsaturated or unsaturated 5- to 7-membered or 5- to 6-membered heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O. Examples which may be mentioned are: azepine, diazepine, indolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, imidazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl or piperidinyl. Preference is given to quinolyl, furyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, piperazinyl, azepine, diazepine, thiazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, tetrahydropyranyl, morphholinyl and thiomorpholinyl.
Preference is given to compounds of the general formula (I) according to the invention
in which
represents straight-chain or branched alkyl having up to 3 carbon atoms,
R2 represents straight-chain alkyl having 5 to 15 carbon atoms or branched alkyl having 3 to 15 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 4 carbon atoms, or represent a straight-chain or branched alkyl chain having up to 6 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 4 carbon atoms and/or by radicals of the formulae xe2x80x94SO3H, xe2x80x94(A)axe2x80x94NR7R8, xe2x80x94Oxe2x80x94Cxe2x80x94NR7xe2x80x2R8xe2x80x2, xe2x80x94S(O)bxe2x80x94R9, HNxe2x95x90SOxe2x80x94R9xe2x80x2, xe2x80x94P(O)(OR10)(OR11), 
xe2x80x83in which
a and b are identical or different and represent a number 0 or 1,
A represents a radical CO or SO2,
R7, R7xe2x80x2l , R8 and R8xe2x80x2 are identical or different and represent hydrogen, or represent phenyl, naphthyl, or pyridyl, where the ring systems listed above are optionally mono- to disubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms, or represent straight-chain or branched alkoxy having up to 4 carbon atoms, or represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, bromine, phenyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a group of the formula xe2x80x94(CO)dxe2x80x94NR14R15,
in which
R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and
d represents a number 0 or 1,
or
R7 and R8 and/or R7xe2x80x2 and R8xe2x80x2 together with the nitrogen atom form a pyrrolidinyl, piperidinyl or morpholinyl ring or a radical of the formula 
xe2x80x83in which
R16 represents hydrogen, phenyl, naphthyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl,
R9 and R9xe2x80x2 are identical or different and represent phenyl or benzyl, or represent straight-chain or branched alkyl having up to 3 carbon atoms,
R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and/or the alkyl chain mentioned above under R3/R4 is optionally substituted by phenyl, naphthyl, morpholinyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl or thienyl, where the radical may optionally also be attached to the alkyl chain via a ring nitrogen atom,
and where aryl and the heterocycle are optionally mono- to disubstituted by identical or different substituents from the group consisting of nitro, fluorine, chlorine, bromine, xe2x80x94SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula xe2x80x94(SO2)exe2x80x94NR18R19,
in which
e represents a number 0 or 1,
R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,
and/or
R3 and R4 represent radicals of the formulae xe2x80x94NR20R21 or xe2x80x94(O)xe2x80x94Exe2x80x94NR22R23,
in which
R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a morpholinyl ring, pyrrolidinyl ring or a radical of the formula 
xe2x80x83in which
R24 has the meaning of R16 given above and is identical to or different from this meaning,
E represents a straight-chain alkylene group having up to 4 carbon atoms,
R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning,
and/or
R3 or R4 represent radicals of the formulae 
xe2x80x83or represent cyclopentyl, cyclohexyl, naphthyl, phenyl pyridyl, or quinolyl or tetrazolyl attached via the phenyl ring,
and where the ring systems given above are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 4 carbon atoms and/or by groups of the formulae xe2x80x94SO3H, xe2x80x94OR26, (SO2)fNR27R28, xe2x80x94P(O)(OR29)(OR30),
in which
R26 represents a radical of the formula 
xe2x80x83represents cyclopentyl or cyclohexyl, or represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to disubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl and halogen,
f represents a number 0 or 1,
R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula xe2x80x94COxe2x80x94NH2,
R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
and/or the ring systems given above are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms, which are optionally substituted by hydroxyl, carboxyl, morpholine, pyridyl or by groups of the formula xe2x80x94SO2xe2x80x94R31, P(O)(OR32)(OR33) or xe2x80x94NR34R35,
in which
R31 represents hydrogen or has the meaning of R9 given above and is identical to or different from this meaning,
R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
R34 and R35 together with the nitrogen atom form a morpholinyl, pyrrolidinyl, piperidinyl ring or a radical of the formula 
xe2x80x83in which
R36 has the meaning of R16 given above and is identical to or different from this meaning,
or
R3 and R4 together with the nitrogen atom form a piperidinyl, pyrrolidinyl or morpholinyl ring, or a radical of the formula 
xe2x80x83in which
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms,
or
R37 represents a radical of the formula xe2x80x94(CO)gxe2x80x94G,
in which
g represents a number 0 or 1,
G represents naphthyl, phenyl, pyridyl or pyrimidyl, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 4 carbon atoms, hydroxyl and trifluoromethyl,
and the heterocycles listed above under R3 and R4 are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms and groups of the formulae xe2x80x94P(O)(OR38)(OR39) or xe2x80x94(CO)g)xe2x80x94NR40R41,
in which
R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
g represents a number 0 or 1,
and
R40 and R41 are identical or different and have the meaning of R18 and R19 given above,
and/or the heterocycles listed under R3 and R4 are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a radical of the formula xe2x80x94SO3H, xe2x80x94NR42R43 or P(O)OR44OR45,
in which
R42 and R43 are identical or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R44 and R45 are identical or different and have the meaning of R10 and R11 given above,
and/or the alkyl is optionally substituted by benzyloxy, naphtyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy and alkylthio having in each case up to 4 carbon atoms, or by a group of the formula xe2x80x94NR42xe2x80x2R43xe2x80x2,
in which
R42xe2x80x2 and R43xe2x80x2 have the meaning of R42 and R43 given above and are identical to or different from this meaning,
and/or the heterocycles listed under R3 and R4 are optionally substituted by phenyl, naphthyl or by radicals of the formulae 
xe2x80x83where the ring systems for their part may be substituted by fluorine, chlorine, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms,
or
R3 and R4 together with the nitrogen atom form radicals of the formulae 
xe2x80x83in which
R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
R45 and R45xe2x80x2 are identical or different and represent hydrogen or methyl,
R46 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, hydroxyl or represent straight-chain or branched alkoxy having up to 4 carbon atoms,
and their salts and isomeric forms.
Particular preference is given to compounds of the general formula (I) according to the invention,
in which
R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R2 represents straight-chain alkyl having 5 to 12 carbon atoms or branched alkyl having 3 to 12 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
R3 and R4 are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 4 carbon atoms, or represent a straight-chain or branched alkyl chain having up to 6 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 4 carbon atoms and/or by radicals of the formulae xe2x80x94SO3H, xe2x80x94(A)axe2x80x94NR7R8, xe2x80x94Oxe2x80x94COxe2x80x94NR7xe2x80x2R8xe2x80x2, xe2x80x94S(O)bxe2x80x94R9, HNxe2x95x90SOxe2x80x94R9xe2x80x2, xe2x80x94P(O)(OR10)(OR11), 
xe2x80x83in which
a and b are identical or different and represent a number 0 or 1,
A represents a radical CO or SO2,
R7, R7xe2x80x2, R8 and R8xe2x80x2 are identical or different and represent hydrogen, or represent phenyl, naphthyl, or pyridyl, where the ring systems listed above are optionally mono- to disubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms, or represent straight-chain or branched alkoxy having up to 4 carbon atoms, or represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, bromine, phenyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a group of the formula xe2x80x94(CO)dxe2x80x94NR14R15,
in which
R14 and R15 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and
d represents a number 0 or 1,
or
R7 and R8 and/or R7xe2x80x2 and R8xe2x80x2 together with the nitrogen atom form a pyrrolidinyl, piperidinyl or morpholinyl ring or a radical of the formula 
xe2x80x83in which
R16 represents hydrogen, phenyl, naphthyl or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl,
R9 and R9xe2x80x2 are identical or different and represent phenyl or benzyl, or represent straight-chain or branched alkyl having up to 3 carbon atoms,
R10 and R11 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
and/or the alkyl chain listed above under R3/R4 is optionally substituted by phenyl, naphthyl, morpholinyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl or thienyl, where the attachment to the alkyl chain may optionally also take place via a ring nitrogen atom,
and where aryl and the heterocycle are optionally mono- to disubstituted by identical or different substituents from the group consisting of nitro, fluorine, chlorine, bromine, xe2x80x94SO3H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula xe2x80x94(SO2)exe2x80x94NR18R19,
in which
e represents a number 0 or 1,
R18 and R19 are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,
and/or
R3 or R4 represents radicals of the formulae xe2x80x94NR20R21 or xe2x80x94(O)xe2x80x94Exe2x80x94NR22R23,
in which
R20 and R21 have the meaning of R18 and R19 given above and are identical to or different from this meaning, or together with the nitrogen atom form a morpholinyl ring, pyrrolidinyl ring or a radical of the formula 
in which
R24 has the meaning of R16 given above and is identical to or different from this meaning,
E represents a straight-chain alkylene group having up to 4 carbon atoms,
R22 and R23 have the meaning of R18 and R19 given above and are identical to or different from this meaning
and/or
R3 or R4 represent the radicals of the formulae 
xe2x80x83or represent cyclopentyl, cyclohexyl, naphthyl, phenyl, pyridyl, or quinolinyl or tetrazolyl attached via the phenyl ring,
and where the ring systems given above are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl and alkoxycarbonyl having in each case up to 4 carbon atoms and/or by groups of the formulae xe2x80x94SO3H, xe2x80x94OR26, (SO2)fNR27R28, xe2x80x94P(O)(OR29)(OR30),
in which
R26 represents a radical of the formula 
xe2x80x83represents cyclopentyl or cyclohexyl, or represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, hydroxyl, carboxyl or phenyl, which for its part may be mono- to disubstituted by identical or different substituents from the group consisting of straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl and halogen,
f represents a number 0 or 1,
R27 and R28 have the meaning of R18 and R19 given above and are identical to or different from this meaning or represent a radical of the formula xe2x80x94COxe2x80x94NH2,
R29 and R30 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
and/or the ring systems given above are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which are optionally substituted by hydroxyl, carboxyl, morpholine, pyridyl or by groups of the formula xe2x80x94SO2xe2x80x94R31, P(O)(OR32)(OR33) or xe2x80x94NR34R35,
in which
R31 represents hydrogen or has the meaning of R9 given above and is identical to or different from this meaning,
R32 and R33 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
R34 and R35 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
R34 and R35 together with the nitrogen atom form a morpholinyl, pyrrolidinyl, piperidinyl ring or a radical of the formula 
xe2x80x83in which
R36 has the meaning of R16 given above and is identical to or different from this meaning,
or
R3 and R4 together with the nitrogen atom form a piperidinyl, pyrrolidinyl or morpholinyl ring, or a radical of the formula 
xe2x80x83in which
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, trifluoromethyl, pyridyl, carboxyl, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms,
or
R37 represents a radical of the formula xe2x80x94(CO)gxe2x80x94G,
in which
g represents a number 0 or 1,
G represents naphthyl, phenyl, pyridyl or pyrimidyl, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, straight-chain or branched alkoxy, alkyl or alkylthio having in each case up to 4 carbon atoms, hydroxyl and trifluoromethyl,
and the heterocycles listed under R3 and R4 are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms and groups of the formulae xe2x80x94P(O)(OR38)(OR39) or xe2x80x94(CO)g)xe2x80x94NR40R41,
in which
R38 and R39 have the meaning of R10 and R11 given above and are identical to or different from this meaning,
g represents a number 0 or 1,
and
R40 and R41 are identical or different and have the meaning of R18 and R19 given above,
and/or the heterocycles listed under R3 and R4 are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyloxy, cyclohexyloxy, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 4 carbon atoms or by a radical of the formula xe2x80x94SO3H, xe2x80x94NR42R43 or P(O)OR44OR45,
in which
R42 and R43 are identical or different and represent hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R44 and R45 are identical or different and have the meaning of R10 and R11 given above,
and/or the alkyl is optionally substituted by benzyloxy, naphtyl or phenyl, which for its part may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy or alkylthio having in each case up to 4 carbon atoms, or by a group of the formula xe2x80x94NR42xe2x80x2R43xe2x80x2
in which
R42xe2x80x2 and R43xe2x80x2 have the meaning of R42 and R43 given above and are identical to or different from this meaning,
and/or the heterocycles listed under R3 and R4 are optionally substituted by phenyl, naphthyl or by radicals of the formulae 
xe2x80x83where the ring systems for their part may be substituted by fluorine, chlorine, hydroxyl or by straight-chain or branched alkyl, alkylthio or alkoxy having in each case up to 4 carbon atoms,
or
R3 and R4 together with the nitrogen atom form radicals of the formulae 
xe2x80x83in which
R44 represents hydrogen or straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
R45 and R45xe2x80x2 are identical or different and represent hydrogen or methyl,
R46 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
R5 and R6 are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, hydroxyl or represent straight-chain or branched alkoxy having up to 4 carbon atoms.
and their salts and isomeric forms.
Particular preference is also given to compounds of the general formula (I) in which
R1 represents methyl or ethyl,
R2 represents straight-chain alkyl having 5 to 11 carbon atoms or branched alkyl having 3 to 11 carbon atoms, or represents cyclopentyl, cyclohexyl, cycloheptyl,
R3 and R4 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, morpholinyl, methoxy, ethoxy, N,N-dimethylamino, N,N-diethylamine or phenyl, which for its part may be substituted up to 3 times by identical or different substituents from the group consisting of methoxy, or represents cyclopropyl, or or represents phenyl which is optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine or hydroxyl, methoxy, ethoxy, fluorine or by straight-chain or branched alkyl having up to 3 carbon atoms, which for its part may be substituted by hydroxyl,
or
R3 and R4 together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring which are optionally substituted by hydroxyl or by radicals of the formulae xe2x80x94P(O)(OC2H5)2 or xe2x80x94CH2xe2x80x94P(O)OH(OC2H5) or by straight-chain or branched alkyl having up to 3 carbon atoms, which for its part may be substituted by hydroxyl or methoxy, or
or
R3 and R4 together with the nitrogen atom form a radical of the formula 
xe2x80x83in which
R37 represents pyrimidyl, ethoxycarbonyl or a radical of the formula xe2x80x94CH2xe2x80x94P(O)(OCH3)2 or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl or methoxy,
R5 represents hydrogen,
and
R6 represents ethoxy,
and their salts and isomeric forms.
Particular preference is furthermore given to compounds of the general formula (I) according to the invention in which R5 represents hydrogen and the ethoxy group is in the O position to the point of attachment of the heterocycle.
Very particular preference is given to compounds according to the invention having the following structures:
Moreover, we have found a process for preparing the compounds of the general formula (I) according to the invention, characterized in that
[A] initially compounds of the general formula (II) 
xe2x80x83in which
R1 and R2 are as defined above
and
L represents straight-chain or branched alkyl having up to 4 carbon atoms, are converted with compounds of the general formula (III) 
xe2x80x83in which
R5 and R6 are as defined above
in a two-step reaction, preferably using the system ethanol and then phosphorus oxytrichloride/dichloroethane, into the compounds of the general formula (IV) 
xe2x80x83in which
R1, R2, R5 and R6 are as defined above,
in a further step reacted with chlorosulphonic acid to give the compounds of the general formula (V) 
xe2x80x83in which
R1, R2, R5 and R6 are as defined above,
and then reacted with amines of the general formula (VI)
HN3R4xe2x80x83xe2x80x83(VI)
in which
R3 and R4 are as defined above
in inert solvents.
The process according to the invention can be illustrated in an exemplary manner by the equations below: 
Solvents which are suitable for the individual steps are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the abovementioned solvents. Particular preference is given to ethanol for the first step and dichloroethane for the second step.
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably of from 0xc2x0 C. to 70xc2x0 C.
The process steps according to the invention are generally carried out under atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example, in a range of from 0.5 to 5 bar).
The reaction to give the compounds of the general formula (V) is carried out in a temperature range of from 0xc2x0 C. to room temperature, and at atmospheric pressure.
The reaction with the amines of the general formula (VI) is carried out in one of the abovementioned chlorinated hydrocarbons, preferably in dichloromethane.
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out at temperatures in a range of from xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably of from 0xc2x0 C. to room temperature.
The reaction is generally carried out at atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example in a range of from 0.5 to 5 bar).
Some of the compounds of the general formula (II) are known, or they are novel, and they can then be prepared by
converting compounds of the general formula (VII)
R2xe2x80x94COxe2x80x94Txe2x80x83xe2x80x83(VII)
xe2x80x83in which
R2 is as defined above
and
T represents halogen, preferably represents chlorine, initially by reaction with compounds of the general formula (VIII) 
xe2x80x83in which
R1 is as defined above
in inert solvents, if appropriate in the presence of a base and trimethylsilyl chloride, into the compounds of the general formula (IX) 
xe2x80x83in which
R1 and R2 are each as defined above,
and finally reacting with the compound of the formula (X) 
xe2x80x83in inert solvents, if appropriate in the presence of a base.
Suitable solvents for the individual steps of the process are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the abovementioned solvents. Particular preference is given to dichloromethane for the first step and to a mixture of tetrahydrofuran and pyridine for the second step.
Suitable bases are generally alkali metal hydrides or alkali metal alkoxides, such as, for example, sodium hydride or potassium tert-butoxide, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or C1-C4 alkylamines, such as, for example, triethylamine. Preference is given to triethylamine, pyridine and/or dimethylaminopyridine.
The base is generally employed in an amount of from 1 mol to 4 mol, preferably from 1.2 mol to 3 mol, in each case based on 1 mol of the compound of the formula (X).
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably of from 0xc2x0 C. to 100xc2x0 C.
The compounds of the general formulae (VII), (VIII), (IX) and (X) are known per se, or they can be prepared by customary methods.
The compounds of the general formula (III) can be prepared by
reacting compounds of the general formula (XI) 
xe2x80x83in which
R5 and R6 are each as defined above
with ammonium chloride in toluene and in the presence of trimethylaluminium in hexane in a temperature range of from xe2x88x9220xc2x0 C. to room temperature, preferably at 0xc2x0 C. and atmospheric pressure, and reacting the resulting amidine, if appropriate in situ, with hydrazine hydrate, to give the compounds of the general formula (III).
The compounds of the general formula (XI) are known per se, or they can be prepared by customary methods.
Most of the compounds of the general formula (IV) and (V) are novel, and they can be prepared as described above.
The amines of the general formula (VI) are known or can be prepared by customary methods.
The compounds of the general formula (I) according to the invention have an unforeseeable useful pharmacological activity spectrum.
They inhibit either one or more of the cGMP-metabolizing phosphodiesterases (PDE I, PDE II and PDE V). This results in an increase of cGMP. The differentiated expression of the phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with the selective inhibitors according to the invention make it possible to selectively address the various cGMP-regulated processes.
Moreover, the compounds according to the invention enhance the activity of substances such as, for example EDRF (endothelium derived relaxing factor), ANP (atrial natriuretic peptide), of nitrovasodilators and all other substances which increase the cGMP concentration in a manner different from that of phosphodiesterase inhibitors.
They can therefore be employed in pharmaceuticals for treating cardiovascular disorders, such as, for example, for treating hypertension, neuronal hypertonia, stable and unstable angina, peripheral and cardial vasculopathies, arrhythmiae, for treating thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transistory and ischaemic attacks, angina pectoris, obstruction of peripheral circulation, prevention of restenoses after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass. Furthermore, they may also be of significance for cerebrovascular disorders.
They are also suitable for treating all disorders in which a relaxing action on smooth muscles is of importance, such as, for example, erectile dysfunction and female sexual dysfunction.
Activity of the Phosphodiesterases (PDEs)
The cGMP-stimulated PDE II, the cGMP-inhibited PDE III and the cAMP-specific PDE IV were isolated either from porcine or bovine heart myocardium. The Ca2+- calmodulin-stimulated PDE I was isolated from porcine aorta, porcine brain or, preferably, from bovine aorta. The cGMP-specific PDE V was obtained from porcine small intestine, porcine aorta, human platelets and, preferably, from bovine aorta. Purification was carried out by anion exchange chromatography over MonoQ(copyright) Pharmacia, essentially following the method of M. Hoey and Miles D. Houslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al., Biochemical Pharmacology, Vol. 35, 1743-1751 (1986).
The xe2x80x9cphosphodiesterase [3H] cAMP-SPA enzyme assayxe2x80x9d and the xe2x80x9cphosphodiesterase [3H] cGMP-SPA enzyme assayxe2x80x9d from Amersham Life Science were used for determining enzyme activity and IC50 values of the various substances. The test was carried out according to the test protocol of the manufacturer. To determine the activity of PDE2, the [3H]cAMP SPA assay was used, and 10xe2x88x926 M cGMP were added to the reaction mixture to activate the enzyme. To measure PDEI, 10xe2x88x927 M calmodulin and 1 mM CaCl2, were added to the reaction mixture. PDE5 was measured using the [3H]cGMP SPA assay.
The substances preferably inhibit phosphodiesterases I and V. For both enzymes, the IC50 values are in the range from 500 to 1 mM for PDE V preferably in the range from 1 to 100 for PDE I preferably in the range from 10 to 300 mM.
In principle, inhibition of one or more phosphodiesterases of this type results in an increase of the cGMP concentration. Thus, the compounds are of interest for all therapies in which an increase in the cGMP concentration is considered to be beneficial.
The cardiovascular effects were investigated using SH rats and dogs. The substances were administered intravenously or orally.
The novel active compounds and their physiologically acceptable salts (for example hydrochlorides, maleates or lactates) can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration of from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration is carried out in a customary manner, preferably orally, transdermally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or inhalatively.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or the type of administration route, on the individual response towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.
For human use, in the case of oral administration, doses of from 0.001 to 30 mg/kg, preferably of 0.01 mg/kg-10 mg/kg are administered. In the case of parenteral administration, it is good practice to use doses of 0.001 mg/kg-xc2xd mg/kg.
The compounds according to the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or their non-toxic salts can be administered in a suitable formulation in accordance with general veterinary practice. Depending on the kind of animal to be treated, the veterinary surgeon can determine the nature of use and the dosage.